These studies are designed to understand the physiological mechanisms that regulate effector cell localization into the liver, which is often a site for metastasis formation and disease induced inflammation. IL-12 and IL-2 are potent immunoregulatory cytokines for natural killer (NK) and T cells, and they induce beneficial antitumor activities in numerous experimental models. The liver, which is often a site for metastasis formation, has been used as a model organ to determine the role of adhesion molecules and endogenous IFN-gamma in the initial recruitment of, and regulatory interactions between, NK and T cells by IL-12 versus IL-2. Daily administration of IL-2 resulted in a progressive increase in NK1.1+(NK) cells, while daily administration of IL-12 caused a rapid increase in NK cells followed by a subsequent decrease coincident with an increase in T cells. In addition, the liver contains a significant population of NK1.1+/CD3+(NK/T) cells that is rapidly lost after the administration of IL-12. The recruitment of NK cells by IL-12 is dependent on IFN-gamma and expression of VCAM-1. Recent studies have shown that IL-12 rapidly induces, in an IFN-gamma dependent manner, expression of the CXC chemokines Mig and Crg-2 in hepatocytes, and that these activated hepatocytes produce factors that are chemotactic for mouse T and NK cells in vitro. Further studies have shown that the hepatocyte-derived chemotactic activity for T cells, but not NK cells, is completely neutralized by a combination of antibodies specific for Mig and Crg-2. Additional studies are now in progress to investigate the differences in mechanism for the leukocyte recruiting effects of IL-2 vs. IL-12 for NK, NK/T, and T cell subsets in the liver The mechanisms by which these subsets can contribute to anti-metastatic effects in the liver are also under study. We have found that both IL-2 and IL-12 have potent anti-metastatic effects against well established liver tumors. We have also found that perforin and to a lesser extent FasL are critical for endogenous resistance to the formation of experimental liver metastases. Studies are now in progress to examine the relationship between changes in leukocyte subsets and antimetastatic effects induced by IL-2 and IL-12, and the molecular mechanisms by which various leukocyte subsets mediate those effects. Overall, these studies should provide a better understanding of the ability of IL-2 and IL-12 to induce NK, NK/T, and T cell recruitment to different tumor and organ sites as well as new insight into the success or failure of biological therapy, and the possible role of parenchymal cells in those processes. The results may also provide insight into mechanisms by which the innate and adaptive immune systems interface for the development of anti-tumor and inflammatory responses. - Adhesion Molecules, Cytokines, Leukocyte Trafficking, NK cell, Tumor Angiogenesis,